PROJECT SUMMARY/ABSTRACT The NIA Interventions Testing Program is a multi-site translational research program to evaluate agents hypothesized to extend mouse lifespan; this part of the program is not under review, and will be expanded 2 fold at each site, as mandated by the RFA. Each site has special skills - mouse expertise and measures of age-sensitive traits at The Jackson Laboratory (Jackson), pathology and statistical analysis at the University of Michigan (UM), and pharmacology/toxicology at the University of Texas Health Science Center at San Antonio (UT) - which will be expanded as mandated by the RFA. Jackson currently supplies diets (control and with interventions added) and performs pilot mouse studies; these jobs will expand. Also, Jackson will routinely supply old, middle-aged and young untreated controls to collaborators, and some positive controls treated with established, effective interventions. In mandated healthspan studies, Jackson will specialize in non- invasive assays to measure changes with age in a variety of physiological systems without harm to the mouse. Treated and control mice will be longitudinally tested at 16 and 22 months of age to follow individual changes with age before disease sets in; most interventions start by 4-10 months, so effects may be detectable by 16 months. Longitudinal testing compared to cross-sectional, permits a more powerful quantification of treatment effects during aging in the genetically heterogeneous UM-HET3 population because genetic variance can be statistically removed. In addition, the relative influence of individual differences in response to the treatment during aging can be quantified. Current plans are to test: body weight; circulating hemoglobin; circulating white blood cell populations, including nave CD4 T cells; short-term memory (5-minute T maze); activity and anxiety (10-minute open field test); grip strength; kidney function (urinary albumin/creatinine ratio); cataracts; collagen aging (tail tendon collagen denaturation); and wound healing (using the incision to remove tail tendon). All tests are designed to minimize stress and optimize quantitative definition of health. Many of these tests have already been shown to change with age in UM-HET3 mice; age-sensitivity will be confirmed for all tests in pilot studies before use with interventions. Benefits of interventions indicated by any of these tests will guide more extensive physiological and biochemical studies, both in the ITP laboratories and elsewhere. Two interventions already shown to extend lifespan in UM-HET3 mice - diet restriction and rapamycin - will be used as positive controls when appropriate.